title: Therapeutic efficacy of AAV1.SERCA2a in monocrotaline-induced pulmonary arterial hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) and alterations in Ca(2+) homeostasis in vascular smooth muscle cells that stimulate proliferation. We, therefore, hypothesized that downregulation of SERCA2a is permissive for pulmonary vascular remodeling and the development of PAH.
  
  
  RESULTS
  SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Overexpresion of SERCA2a in human pulmonary artery endothelial cells in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno-associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and fibrosis in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying β-galactosidase or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of monocrotaline administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling in comparison with rats administered AAV1 carrying β-galactosidase or saline.
  
  
  CONCLUSIONS
  Downregulation of SERCA2a plays a critical role in modulating the vascular and right ventricular pathophenotype associated with PAH. Selective pulmonary SERCA2a gene transfer may offer benefit as a therapeutic intervention in PAH.
authors.affiliation: Cardiovascular Research Center, Box 1030, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, New York, NY 10029, USA. lahouaria.hadri@mssm.edu
authors.forename: Lahouaria
authors.initials: L
authors.lastname: Hadri
authors.forename: Razmig G
authors.initials: RG
authors.lastname: Kratlian
authors.forename: Ludovic
authors.initials: L
authors.lastname: Benard
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Maron
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.forename: Dennis
authors.initials: D
authors.lastname: Ladage
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Jaume
authors.initials: J
authors.lastname: Aguero
authors.forename: Borja
authors.initials: B
authors.lastname: Ibanez
authors.forename: Irene C
authors.initials: IC
authors.lastname: Turnbull
authors.forename: Erik
authors.initials: E
authors.lastname: Kohlbrenner
authors.forename: Lifan
authors.initials: L
authors.lastname: Liang
authors.forename: Krisztina
authors.initials: K
authors.lastname: Zsebo
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawase
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Jane A
authors.initials: JA
authors.lastname: Leopold
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D065627:Familial Primary Pulmonary Hypertension; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology / Q000628:therapy*; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D016686:Monocrotaline; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human
keywords: calcium; gene therapy; heart failure; muscle, smooth; pulmonary hypertension; ventricular remodeling